My laboratory is involved in studies to genetically modify autologous lymphocytes to improve their anti-tumor activity. In 1990 we reported the first studies of gene transfer in humans which involved the adoptive transfer of TIL transduced with a marker gene encoding neomycin phosphotransferase. These studies suggested the possibility that genes could be inserted into lymphocytes to improve their anti-tumor efficacy using high efficiency retroviral gene insertion. In clinical studies we showed that up to 30% of patients with metastatic melanoma will achieve objective clinical cancer regressions when treated with their autologous lymphocytes transduced with T cell receptors that recognized the MART-1 or gp100 melanoma antigens. These were the first studies showing that TCR transduced lymphocytes could mediate cancer regression. T-cell receptors were identified that recognized NY-ESO-1 and MAGE-A3, the cancer germ-live antigens, epitopes that have also been used to mediate cancer regression inpatients. Using cells transduced with a TCR reactive with the NY-ESO-1 cancer testesantigen 10 of 19 melanoma patients and 10 of 15 synovial cell sarcoma patients have had objective responses. Current clinical trials involve the administration of cells transduced with antigens encoding T-cell receptors that recognize random somatic mutations. T-cells that recognize random somatic mutations have been identified in 82% of 99 patients with a variety of solid epithelial cancer. 197 neoantigens were identified all of which were unique except for two patients that recognized a KRAS G12D mutation. Chimeric antigen receptors have been developed that recognize CD19 cell surface antigens on B cell malignancies and clinical trials using the transfer of these cells have moderated objective responses in 56% of patients with Diffuse Large B-cell Lymphoma including 50% with durable complete responses. Studies of T-cell transfer targeting the EGFRvIII mutation' expressed on glioblastomas showed no responses in 18 patients.